Symptoms and Severity of COVID-19 in Patients with Immune-Mediated Inflammatory Diseases: Experience of a University Medical Center

Background The pandemic situation of the novel coronavirus (severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)) and its associated disease (coronavirus disease 2019 (COVID-19)) represents a challenging condition with a plethora of aspects. The course of COVID-19 in patients with immune-mediated inflammatory diseases (IMID) such as inflammatory bowel disease (IBD) and rheumatic diseases (RD) is not well known. Our study is one step toward closing this gap by collecting data on vaccination rates, infection-free survival, and individual symptom severity. Methods We conducted a prospective questionnaire-based study between April 2022 and October 2022 at our university hospital. Outward patients over the age of 18 years were screened for participation and reported about their infection/infection-free survival since the start of the pandemic. Results Finally, 156 patients were included in the study, 117 (75.0%) of which had inflammatory bowel disease and 39 (25.0%) patients with rheumatic disease. Altogether, 143 (91.7%) persons had received at least one vaccination against SARS-CoV-2. A total of 153 patients provided information regarding their COVID-19 history: 81 patients (52.0%) self-reported about their SARS-CoV-2 infection. In general, courses of infection were mild: only two patients (2.5% of patients with reported COVID-19) were hospitalized due to COVID-19 with one (1.2%) of the two needing intensive care. Asymptomatic COVID-19 had been described by 7 persons (8.6% of patients with reported COVID-19). Acute COVID-19 was accompanied by fatigue/tiredness in 58 persons (71.6% of patients with history of COVID-19) as the most frequent symptom. Other complaints were common cold (55 patients = 67.9%), cough (51 patients = 63.0%), headache (44 patients = 54.3%), and fever (35 patients = 43.2%). Stratified by vaccination status (unvaccinated vs. at least once vaccinated), the time to infection differed significantly (logrank test: p = 0.04, Chi2 4.1). At least once vaccinated people had a median COVID-19-free survival of 28.5 months (confidence interval (CI): 23.6 months-not reached). Without any vaccination, the estimated time to infection was 25.1 months (CI: 23.6 months-not reached). Conclusion Our IMID patients have a high rate of vaccination against SARS-CoV-2. Data show a significantly longer infection-free survival in vaccinated IMID patients as compared to unvaccinated patients. Discrimination between symptoms of COVID-19 and a concomitant inflammatory disease is difficult as complaints might be overlapping. This trial is registered with DRKS00028880.


Introduction
At the end of 2019, a series of atypical pneumonia cases in Wuhan, the capital of Hubei Province in the People's Republic of China, had evolved.Te cases spread, evolving to an epidemic throughout China, and fnally to an increasing number of cases worldwide.Within weeks, the causal agent was found in a novel coronavirus (severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)).In February 2020, the World Health Organization named the associated infective illness coronavirus disease 2019 (COVID-19) [1].
By now (October 2023), 677 million cases of COVID-19 have been counted around the world, resulting in 6.9 million associated deaths [2].In Germany, 37 million SARS-CoV-2 infections were reported.Te German Free State of Saxony, where our study was conducted, has been heavily afected by COVID-19 with 2 million cases out of 4 million inhabitants [3].
Te clinical course of COVID-19 is highly variable: a notable number of asymptomatic people (about 33%) face 14% of patients with severe disease (i.e., dyspnea and/or hypoxia).In 5% of cases, the disease takes a critical course with respiratory failure or shock and in 2.3% the disease ends fatally [4][5][6].Not only the severity of COVID-19 but also the spectrum of symptoms varies: cough, myalgias, and headache are most frequently reported.Other commonly described symptoms are diarrhoea, sore throat, anosmia/taste disorders, and joint pain.Te proven involvement of distinct organ systems has led to the understanding of COVID-19 as a multisystem disorder [7].Te critical point of pathogenesis seems to be a dysregulated immune system, which results in hyperinfammation [8,9].
Immune-mediated infammatory diseases (IMID) represent a broad and heterogenic group of chronic illnesses with partially overlapping pathogeneses.Even within the afected organ system, there is distinct manifestation, leading to further subclassifcation (e.g., gastrointestinal: Crohn's disease, ulcerative colitis; rheumatic: rheumatoid arthritis, axial spondyloarthritis, systemic lupus erythematosus, psoriatic arthritis, granulomatosis with polyangiitis; ophthalmologic: noninfectious uveitis and dermatologic: psoriasis) [10].About 4.5% of the world's population is afected by IMID [11].Due to the underlying condition on the one hand and immunosuppressive therapy of which, on the other hand, infectious diseases are in general more frequent and more severe in IMID patients [12,13].Te efects of COVID-19 on this huge patient collective have been a critical aspect of the COVID-19 pandemic.Prevalence, severity, and lethality of COVID-19 seem to range in the level of the general population.Controlled IMID is regarded as being protective against severe course of COVID-19 [12,14,15].Pharmacologic immunosuppression seems no risk factor for SARS-CoV-2 susceptibility [16].A clear connection between the severity of COVID-19 and immunosuppressive agents for IMID is not established as the data are contradictory.Higher systemic steroid dosage (e.g., prednisone ≥10 mg/day) and B cell depletion by rituximab seem to be associated with worse course and outcome of COVID-19 [14,[17][18][19][20][21][22][23].
Due to this lack of knowledge, our center initiated this study to systemically collect missing data.

Methods
We conducted a monocentric investigator-initiated trial at our tertiary medical center.Outpatients over the age of 18 years and established diagnosis of immune-mediated infammatory disease (IMID) were screened.Excluded were patients not capable or willing to provide information about their SARS-CoV-2 infection/COVID-19 since the start of the pandemic.Data are collected by a self-flled form in the German language.Screening and recruitment (equals questionnaire completion) took place between April 2022 and October 2022 (Figure 1).In case a patient entered twice during a separate appointment, only the latest questionnaire got into further analysis.
Te project was performed in accordance with guidelines for good clinical practice (GCP, E6/R1) and the ethical guidelines of the Helsinki Declaration.Approval was given by the local ethics committee (Faculty of Medicine, Leipzig University Medical Center, internal reference number 013/ 22-ek).Informed written consent was obtained from every participant.No beneft (fnancial/nonfnancial) was provided in return for study participation.Missing willingness or capability for participation meant no disadvantage with regard to further treatment.Tis study had been recorded in the German Clinical Trials Register (identity document DRKS00028880).No external funding had been raised.
Symptoms of COVID-19 were asked in multiple-choice format.A selection of common clinical features was made after literature research [24,25].More than one answer was possible.Additional features could be entered in written form.A special defnition/threshold for a symptom (e.g., measured body temperature to be set as fever) was not given.Subjective estimation was sufcient.
Types of vaccination against SARS-CoV-2 had been checked by multiple-choice questions as well.We preselected the four authorised vaccines that had been authorised by the European Medicines Agency (EMA) at the time of study conception (December 2021): Comirnaty

® by
BioNTech/Pfzer, Spikevax ® by Moderna Biotech, Vaxzevria ® by AstraZeneca, and Jcovden ® by Johnson&- Johnson/Janssen-Cilag International NV [26].A single selection for the vaccine could be made from frst to fourth vaccination.Free-text felds had been retained each time.
Te attending physician flled in the features regarding IMID (e.g., time of diagnosis, extent, and pharmacological therapy) on base of their knowledge and each individual's medical records.Prednisone and prednisolone doses were considered equal glucorticoid strength [27,28].
Statistics and graphics were carried out by open access software "R," version 4.1.1(Te R Foundation for Statistical Computing, USA).Chi-squared (Chi 2 ) testing with Yates' continuity correction checked for independence between compared subgroups.A two-sided t-test has been performed for continuous variables.Welch modifcation of the t-test was used if Levene's test showed inequality of variance [29].
Time-to-event analysis regarding the onset of individual COVID-19 was managed by Kaplan-Meier method [30,31].Te starting point for each individual was set to the 27th of January 2020, the date of the frst proven SARS-CoV-2 infection in Germany [32].Te diference between subgroups is calculated by logrank testing [33].Te reverse Kaplan-Meier estimator calculated the median follow-up [34].
P value below fve percent was noted as a criterion regarding statistical signifcance.
More women (n = 89; 57.1%) than men (n = 67; 42.9%) were part of our IMID cohort.Te median and mean age at the survey were 42 and 46 years, respectively.Te youngest patient was aged 18 years, and the oldest patient was 95 years.Most of the patients reported at least one vaccination against SARS-CoV-2 (n = 143; 91.7%).Ten patients (6.4%) did not receive any vaccination against COVID-19, and three patients (1.9%) did not provide the requested information (Table 2).Administered vaccines were mainly mRNA-based with 127 persons having received Comirnaty ® or Spikevax ® ; twelve patients had been vaccinated by a doctor with Vaxzevria ® , and four patients with Jcovden ® in their frst course of SARS-CoV2-vaccination.A second dose of vaccination was reported by 136 IMID patients (87.1%; 4 x Vaxzevria ® , 113 x Comirnaty ® , 18 x Spikevax ® , and 1 x Unknown).Tree vaccinations were declared by 113 persons (72.4%; 3 x Vaxzevria ® , 83 x Comirnaty ® , 25 x Spikevax ® , and 2 x Unknown).Finally, four vaccines were given to ten IMID patients (6.4%; 8 x Comirnaty ® and 2 x Spikevax ® ; Table 3, Figure 2).COVID-19 was self-reported in 81 (51.9%)IMID patients, and the associated SARS-CoV-2 infection was mainly detected by positive polymerase chain reaction (n � 68; 83.9%,Table 4).Tree patients did not answer this topic, and 72 persons had no proven and/or suspected COVID-19.Te severity of COVID-19 appeared rather mild with only one person in need of intensive care and one further in the inpatient setting.Among the 81 persons with a history of COVID-19, the majority (n � 64; 79.0%) received no special treatment and a smaller fraction (n � 15; 18.5%) had been treated as an outpatient (e.g., general practitioner, Table 5).
Pharmacological therapy for IMID was quite heterogenic in both subgroups of patients with and those without a history of COVID-19 (Table 10).Azathioprine was used in 12 patients (14.8%) with and in 11 patients (15.3%) without self-reported COVID-19 (p � 1).

Autoimmune Diseases
Methotrexate has been established in fve patients each (6.2% with vs. 6.9 without COVID-19 history, p � 1).In the COVID-19 cohort, three patients (3.7%) were taking hydroxychloroquine; contrary to that, one person (1.4%) was without reported SARS-CoV-2 infection.Persons on biological agents built a main group in our cohort with 35 patients (43.2%) being treated in the COVID-19 cohort vs. 36 patients (50%) with concomitant biologic and lack of COVID-19 history (p � 0.50).An in-depth analysis of biologic agents was not computed due to the heterogeneity of pharmacological principles and relatively low absolute numbers.Systemic glucocorticoid therapy was less frequently used within the COVID-19 cohort (13.6% vs. 30.6%,p � 0.02) but at comparable dosages (mean 10.5 vs. 10.3 mg, p � 0.98, Table 11).
Some therapeutic substances are only reported within one patient cohort (IBD or RD).Tis is due to diseasespecifc efcacy and/or labeled use (e.g., mycophenolate was exclusively used in RD patients).

. Discussion
Te ongoing COVID-19 pandemic challenges our health system on an extreme scale.A systematic report on a welldescribed cohort of people with immune-mediated      We report a high percentage of people with vaccination against SARS-CoV-2; 91.7% were at least once vaccinated.Tis fnding stands out under the background of much lower immunization rates in Germany (78%) and in our federal state (66%); percentages refer to a fraction of the population, who had received at least one SARS-CoV-2 vaccine.Data were retrieved by the 26th of September 2022, representing the date of the last screened patient [35].Given the absence of mandatory population-wide vaccination programs, we interpret this as an expression of the high will of IMID patients towards SARS-CoV-2 vaccination.Te presence of an IMID as an underlying chronic disease might serve as an incentive towards vaccine administration because certain preexisting comorbidities are associated with more severe courses of COVID-19 [36,37], and although IMID has not been shown as an independent risk factor, mainstream media reported broadly over COVID-19 severity in otherwise chronically ill patients.Tis might have lowered vaccination thresholds [38].Besides, federal health recommendations addressed people with an autoimmune disorder and/or rheumatic disease within their very frst nationwide publications: rheumatic and IBD patients were together considered as highly prioritised for SARS-CoV-2 vaccination [39,40].Furthermore, a relevant fraction of IMID patients have immunosuppressive comedication, which can be found in our cohort as well.Tis represents an established risk factor for severe COVID-19 and might be another individual reason towards vaccination [36,37].Finally, our cohort represents persons with a certain willingness for medical advice and guidance as they per se are part of our outpatient ward.Tis might stand for a proper health awareness and a tendency towards preventive measurements such as vaccinations.In accordance with that, high SARS-CoV-2 vaccination coverage is reported in RD patients [41].

Autoimmune Diseases
Te mRNA-based vaccines (Comirnaty ® and Spikevax ® ) and the viral vector vaccine Jcovden ® have a similar administration schedule, which includes injections of two doses within four to six weeks as a primary immunization course.Te other viral vector vaccine (Vaxzevria ® ) only needs one administration for basic immunization, and this could be one reason that it was solely reported in the frst round of vaccination (Table A8 and Figure 2).Another  Autoimmune Diseases reason for the dominance of mRNA vaccines over vector vaccines might have been the restrictive recommendation for the latter that came up around April 2021, due to thromboembolic complications following vaccination [39].
In general, administration recommendations for all four vaccines regarding primary immunization and booster are quite similar [42].Tat is why we summarized all patients, who had received at least one authorised vaccine, into one subgroup when stratifed regarding self-reported COVID-19.Tis method, of course, neglected diferences in vaccine efectiveness: a large case-control study detected a signifcantly higher efcacy of mRNA vaccines (Spikevax ® 93%/ Comirnaty ® 88%) compared to the vector vaccine Jcovden ® (71%) regarding COVID-19 hospitalization [43].
Our results suggest that IMID patients with at least one vaccination against SARS-CoV-2 had a longer COVID-19free survival.High efcacy against laboratory-proven COVID-19 has been reported (Spikevax ® 96%/Com- irnaty ® 95%/Jcovden ® 75%, one month after basic im- munization) [44].Although it might be impaired by some drugs such as rituximab, vaccine efcacy was also demonstrated in patients with rheumatic infammatory diseases under immunosuppressive treatment [45].Interestingly, our fnding seems to be supported by our analysis although several possible confounders are not considered: frst of all, heterogeneity between the two groups (once vaccinated vs. unvaccinated) was not checked.Vaccination status and vaccine type have not been regularly verifed by medical documentation and/or laboratory results (e.g., antibody detection).Memory bias might have impaired recall of vaccination type/status.However, we estimate that false recollection is rather unlikely in this issue, as discussions over SARS-CoV-2 vaccination dominated a broad and lively debate in the individual and society's context.Moreover, vaccination status had to be recalled on a regular basis in daily activities (access to public places).On the other hand, some people, who stated absence of COVID-19 in their history, might have been infected with SARS-CoV-2 but were not tested; e.g., due to lack of symptoms, no available test or missing will for testing because of individual reasons (to avoid quarantine).In general, social desirability might as well have infuenced the answer of infection/vaccination status, as patients in this nonanonymous survey could have tended to fulfl presumed answers [46].Te time of vaccination administration was also not considered.Tis might explain diferences in infection protection by waning immunity over time [47][48][49][50].Additionally, diferent SARS-CoV-2 variants, with distinct clinical features regarding breakthrough infection and reinfection rate due to immune evasion, were predominantly circulating during a pandemic and are not recorded in our time-to-event analysis [51].Te fnding that the patients with a history of SARS-CoV-2 infection had lower age than the ones without a history of COVID-19 is consistent with epidemiological data that the younger population was earlier afected within the course of the pandemic.More social interaction (educational/work duties and cultural gatherings) and fewer social restrictions for these groups could be the underlying reason [2].
Te hospitalization rate seems quite low with only two out of 81 COVID-19 patients (2.5%).A higher hospitalization rate had been reported earlier with an estimation of 14% [25], but this dates back to the beginning of 2020 at a very early course of the pandemic: insecurities and concerns about this novel disease might have led to a low threshold towards inpatient admission.Younger data give a hospitalization rate of around 2.1%, which appears consistent with our proportion [52].Furthermore, the SARS-CoV-2 vaccination rate in the general population and specifcally in our cohort (91.7% at least once vaccinated) surely leads to relevant protection from severe COVID-19 courses.Additionally, the disease severity of COVID-19 decreased with the occurrence of new variants such as omicron [53,54].Other confounding factors (e.g., comorbidities besides IMID) for the course of COVID-19 were not considered in our statistical estimations-mainly due to very low absolute numbers (Table 12)-but at least demographic factors of our analysed patients are coherent when compared to population-based studies regarding IMID [55][56][57][58].Fatal courses were obviously not detected as a deceased patient would not have been able to attend scheduled appointments and be screened for this study.However, none of our physician staf noticed or had been informed about a single IMID patient who had died in direct association with COVID-19.
Terapeutic steroid use in COVID-19 is a huge and extensively studied issue of the pandemic.Downregulation of a pathogenic cytokine storm was discussed as benefcial in certain subgroups during acute COVID-19 [59].Nevertheless, chronic steroid use-which means pre-existing to SARS-CoV-2 infection-was associated with symptomatic disease and risk for a severe course of COVID-19.Tat could be shown in people with rheumatic diseases, in the IBD population and in nationwide studies [18,23,60].An increased risk of symptomatic infection has been derived from these fndings.However, data for a higher susceptibility to SARS-CoV-2 under prior steroid use are lacking.Due to the nature of COVID-19 with inconsistent testing strategies and high rates of asymptomatic infections, standard epidemiological methods hardly might ever close that gap of knowledge.On the other hand, steroid recipients-like in our cohort-might be more likely to adhere to isolation precautions, thereby reducing their overall exposure which leads to underestimation of their susceptibility to SARS-CoV-2.Tis could analogously in our case, lead to an association of protective systemic steroid therapy with regard to COVID-19.
Symptoms of COVID-19 and IMID condition might interfere: diarrhoea as a typical fnding in IBD patients and muscle/joint pain in rheumatic patients are reported as a COVID-19 symptom in the general population, in IMID patients and in our study as well [24,25,61,62].Especially musculoskeletal symptoms are very common in post-COVID-19 patients too: approx.30% of post-COVID-19 patients fulfl the criteria for fbromyalgia [63].Answers in that particular context have to be taken very cautiously.Te distinction between IMID disease fares and COVID-19 is, therefore, considered very challenging.Involved medical 8 Autoimmune Diseases associations tried to face this issue with guideline recommendations [64][65][66].Post hoc estimation of whether IMID activity and/or COVID-19 was contributing to the abovementioned specifc symptoms could not be addressed by our study approach and required a more objective methodology.Global quality of life had been assessed as a visual analogue scale: a history of COVID-19 did not seem to have an infuence on that specifc topic (data not shown).
Tese biases were a principal problem of this self-reported, questionnaire-based study: the long time since the course of COVID-19 might have limited memory of specifc symptoms at that time.Further relevant limitation is given through the monocentric approach of our study, which might have led to a selection bias.Besides, as the study was conducted by our gastroenterologic/rheumatic ward, no further localization of the IMID spectrum, such as ophthalmologic or dermatologic involvement, is presented.Tis might limit generalisability, but nevertheless, our study approach gives a good overview of the situation in a signifcant patient collective.Additionally, our study is conceptualized prospectively which improves information quality in general, although individual data collection has to be seen in retrospect.
IMID patients represent a special population in the context of COVID-19.Our study presents an overview of a large-scale medical center during a pandemic situation to elucidate this topic.Autoimmune Diseases

Figure 3 :
Figure 3: Distribution and frequency of symptoms in COVID-19.COVID-19: coronavirus disease 2019; the most frequently reported symptoms are presented, sorted decreasingly by cumulative incidence.

Table 1 :
Patient distribution of rheumatic and infammatory bowel diseases.

Table 10 :
Systemic pharmacotherapy for the immune-mediated infammatory disease at the time of survey.

Table 11 :
Systemic glucocorticoid therapy of IMID patients at the time of survey.